Identification of novel MYH14 variants in families with autosomal dominant sensorineural hearing loss.

Autosomal dominant sensorineural hearing loss (ADSNHL) is a genetically heterogeneous disorder caused by pathogenic variants in various genes, including MYH14. However, the interpretation of pathogenicity for MYH14 variants remains a challenge due to incomplete penetrance and the lack of functional studies and large families. In this study, we performed exome sequencing in six unrelated families with ADSNHL and identified five MYH14 variants, including three novel variants. Two of the novel variants, c.571G > C (p.Asp191His) and c.571G > A (p.Asp191Asn), were classified as likely pathogenic using ACMG and Hearing Loss Expert panel guidelines. In silico modeling demonstrated that these variants, along with p.Gly1794Arg, can alter protein stability and interactions among neighboring molecules. Our findings suggest that MYH14 causative variants may be more contributory and emphasize the importance of considering this gene in patients with nonsyndromic mainly post-lingual severe form of hearing loss. However, further functional studies are needed to confirm the pathogenicity of these variants.

Genetic, Surgical and Oncological Approach to Breast Cancer, with BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 Variants.

Objective: The aim of this study was to determine the frequency of germline variants in BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 in patients admitted to a medical genetics clinic with breast cancer and to assess these identified variants according to published genetic, surgical and oncological perspectives. Materials and Methods: Medical history, and cancer diagnosis information for 195 independent probands with operated breast cancer were collected from requisition forms and medical records. The exonic regions and exon-intron junctions in BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 genes were sequenced. Analysis of fastq files was performed on the Qiagen Clinical Insight-Analyse Universal with panel-specific pipeline and vcf files were interpreted clinically using Qiagen Clinical Insight-Interpret. Results: Gene variants (pathogenic, likely pathogenic and variants of unknown significance) were detected in 53 (27.2%). Detailed information about the patients (age of diagnosis, family history, gender), cancer stage, tumour characteristics (ER, PR, human epidermal growth factor receptor 2 status) and all information related to the detected variants (gene, location, nucleotide and amino acid change, exon number, impact, mutation classification, dbSNP number and HGMD variant class) were assessed. In total, 58 mutations were identified including 14 novel, previously unreported variants. Conclusion: Molecular characterization and identification of mutations have important implications for predictive, preventive, and personalized medicine, including genetic counseling and development of specific treatment protocols. We emphasize variants of unknown significance (VUS) as the clinical significance of VUS changes over time and variant classification is important for clinical molecular genetic testing and clinical guidance. This study may provide new insights into risk assessment for variants in CDH1, PALB2, PTEN and TP53, in addition to BRCA1 and BRCA2, which may prove useful for clinical management of breast cancer patients. Further studies are needed to identify the common gene variants in the Turkish population and evaluate the pathogenity of VUS.

Mitochondrial Mutations in Multiple Sclerosis Patients with Atypical Optic Neuropathy.

BACKGROUND: Multiple sclerosis-related optic neuritis is mostly associated with good recovery. The aim of this study was to investigate the causes of progressive visual worsening in multiple sclerosis patients despite treatment. METHODS: We retrospectively reviewed the medical records of multiple sclerosis patients with optic neuritis admitted to the ward of our Neurology Department between 2001 and 2020. The patients with unilateral/bilateral progressive visual loss or non-substantial recovery of visual acuity were screened for genetic testing for Leber's hereditary optic neuropathy. RESULTS: Of 1014 multiple sclerosis patients, 411 (39%) reported having optic neuritis. During follow-up, 11 patients manifested atypical characteristics of multiple sclerosis-related optic neuritis (presence of one of the following clinical findings: bilateral simultaneous or sequential eye involvement, progressive visual loss, or no response to corticosteroids during hospitalization), while others presented with typical multiple sclerosis-related optic neuritis. Those multiple sclerosis patients with atypical characteristics of optic neuritis were screened for other possible etiologies of optic neuropathy. We found pathogenic mitochondrial mutations in 5 patients with multiple sclerosis in our study group. CONCLUSION: In our study group, the prevalence of mitochondrial mutations among all multiple sclerosis patients with optic neuritis was 0.12%. We strongly recommend investigating Leber's hereditary optic neuropathy mutations in MS patients if they suffer from severe or bilateral visual loss without recovery during follow-up. Because Leber's hereditary optic neuropathy mitochondrial mutations indicate relatively poor visual prognosis and have important implications for genetic counseling.

Radixin modulates the function of outer hair cell stereocilia.

The stereocilia of the inner ear sensory cells contain the actin-binding protein radixin, encoded by RDX. Radixin is important for hearing but remains functionally obscure. To determine how radixin influences hearing sensitivity, we used a custom rapid imaging technique to visualize stereocilia motion while measuring electrical potential amplitudes during acoustic stimulation. Radixin inhibition decreased sound-evoked electrical potentials. Other functional measures, including electrically induced sensory cell motility and sound-evoked stereocilia deflections, showed a minor amplitude increase. These unique functional alterations demonstrate radixin as necessary for conversion of sound into electrical signals at acoustic rates. We identified patients with RDX variants with normal hearing at birth who showed rapidly deteriorating hearing during the first months of life. This may be overlooked by newborn hearing screening and explained by multiple disturbances in postnatal sensory cells. We conclude radixin is necessary for ensuring normal conversion of sound to electrical signals in the inner ear.

Treatment of three hereditary leiomyomatosis patients with cryotherapy.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas (CLM), uterine leiomyomas, and the increased risk of renal cell carcinoma. Piloleiomyomas develop from the arrectorpili muscle and are usually painful. For 22% of the affected patients, the pain is reported to impair their life quality. Since there are few case reports about cryotherapy for cutaneous leiomyomas in the literature, we have decided to present three patients who had painful cutaneous leiomyomas treated with cryotherapy.

Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss.

We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.

Research of genetic bases of hereditary non-syndromic hearing loss.

AIM: Hearing loss is the most common sensory disorder that affects approximately one per 1000 live births. With this project, we aimed to identify gene variants that were common causes of hearing loss in Turkey to contribute to the planning of genetic screening programs for hearing loss, as well as to improve genetic counseling to affected families. MATERIAL AND METHODS: Twenty-one families with at least two affected individuals and parental consanguinity who presented with non-syndromic severe-to-profound sensorineural hearing loss were included in this study. We first screened for mutations in GJB2 and mitochondrial DNA 12S RNA genes. Subsequently, we genotyped the TMIE c.250C>T and SNP markers flanking the SLC26A4, MYO7A, MYO15A, OTOF, CDH23, TMIE, TECTA, PCDH15, TMC1, TMPRSS3, TMHS genes in the remaining twelve families without mutations in GJB2. RESULTS: Screening for mutations in GJB2 gene showed c.[35delG];[35delG] mutation in four families, c.[35delG];[507C>A] mutation in two families, c.[35delG];[-23+1G>A] mutation in one family, and c.457G>A heterozygous mutation in one family. Genotyping SNP markers showed the c.[250C>T];[250C>T] mutation in TMIE in one family. A homozygous region with SNP genotypes was detected with the OTOF gene in one family, the TMPRSS3 gene in another family, and also a homozygous region was detected with TMHS, OTOF, and TMPRSS3 genes in another family. CONCLUSIONS: Further research will be required to determine the genetic bases of hearing loss in families with non-syndromic hearing loss.

The effect of parental 5,10-methylenetetrahydrofolate reductase 677C/T and 1298A/C gene polymorphisms on response to single-dose methotrexate in tubal ectopic pregnancy.

OBJECT: The aim of this study was to assess the effect of parental 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C/T and 1298A/C) on response to single-dose methotrexate (MTX) treatment in tubal ectopic pregnancy (TEP). MATERIALS AND METHODS: In this prospective cohort study, cases with unruptured TEPs were grouped into two according to their response to single-dose MTX treatment (Group 1: responsive, n:88; Group 2: unresponsive, n:21). The groups were compared with regard to baseline demographic and clinical parameters. As a main outcome measure, the independent effects of parental MTHFR gene polymorphisms on response to single dose MTX treatment were evaluated. RESULTS: One hundred and nine unruptured TEP were included in the final analysis. The mean maternal age was 29.30 ± 5.21 years, gravity 2 (min-max: 1-5), parity 1 (min-max: 0-4). The median serum beta-human chorionic gonadotropin (ß-hCG) was 1403.35 MI/I (Q1-Q3: 517-2564). The overall response rate was 81% (88/109). The groups were similar with respect to basic baseline demographic data and serum ß-hCG level. Binary logistic regression analysis showed that the presence of parental MTHFR677C/T and 1298A/C polymorphism were not independent factor predicting treatment success (p > 0.05). The only independent factor for resistance to single dose MTX was the previous TEP (OR: 4.47 (1.18-16.9)). CONCLUSION: Parental MTHFR 677C/T and 1298A/C mutations do not predict the outcome of single dose intramuscular MTX treatment in unruptured TEP.

The effect of the additional cytogenetic abnormalities on major molecular response and BCR-ABL kinase domain mutations in long-term follow-up chronic myeloid leukemia patients, a cross sectional study.

The aim of the study was to examine the relation between additional chromosomal aberrations (ACAs) with major molecular response (MMR) and BCR-ABL kinase domain (KD) mutations in the long-term follow-up of the chronic myeloid leukemia (CML) disease. The study design was cross-sectional observational and used the CML patients' data of Izmir Ataturk Education and Research Hospital from 2011 to 2015. Conventional cytogenetic, fluorescence in situ hybridization (FISH), quantitative real-time polymerase chain reaction (RQ-PCR) test results from 89 CML patients' and pyrosequencing analysis results from 17 patients' were set up for comparison analysis. The chi-square test was used in statistical analysis of the experimental data. There were no statistically significant correlations between ACAs and MMR (p = .361, p > .05) groups or BCR-ABL KD mutations (p = .576, p > .05) groups observed in the study. This study has revealed that MMR and BCR-ABL KD mutations did not correlate with ACAs.

Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort.

PURPOSE: Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES). METHODS: After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes. RESULTS: We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects. CONCLUSION: We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364-371.

Novel domain-specific POU3F4 mutations are associated with X-linked deafness: examples from different populations.

BACKGROUND: Mutations in the POU3F4 gene cause X-linked deafness type 3 (DFN3), which is characterized by inner ear anomalies. METHODS: Three Turkish, one Ecuadorian, and one Nigerian families were included based on either inner ear anomalies detected in probands or X-linked family histories. Exome sequencing and/or Sanger sequencing were performed in order to identify the causative DNA variants in these families. RESULTS: Four novel, c.707A>C (p.(Glu236Ala)), c.772delG (p.(Glu258ArgfsX30)), c.902C>T (p.(Pro301Leu)), c.987T>C (p.(Ile308Thr)), and one previously reported mutation c.346delG (p.(Ala116ProfsX26)) in POU3F4, were identified. All mutations identified are predicted to affect the POU-specific or POU homeo domains of the protein and co-segregated with deafness in all families. CONCLUSIONS: Expanding the spectrum of POU3F4 mutations in different populations along with their associated phenotypes provides better understanding of their clinical importance and will be helpful in clinical evaluation and counseling of the affected individuals.

A Glutamine Repeat Variant of the RUNX2 Gene Causes Cleidocranial Dysplasia.

Cleidocranial dysplasia (CCD), an autosomal dominant skeletal dysplasia characterized by hypoplastic clavicles and delayed closure of the cranial sutures, is caused by mutations of the runt-related transcription factor 2 (RUNX2) gene. The RUNX2 gene consists of a glutamine and alanine repeat domain (Q/A domain, 23Q/17A), a DNA-binding Runt domain and a proline/serine/threonine-rich domain. We report on a familial case of CCD with a novel mutation within the Q/A domain of the RUNX2 gene, which is an insertion in exon 1 (p.Q71_E72insQQQQ) representing the Q-repeat variant (27Q/17A). Functional analysis of the 27Q variant revealed abolished transactivation capacity of the mutated RUNX2 protein. This is the first case report that demonstrated a glutamine repeat variant of the RUNX2 gene causes CCD.

Emopamil binding protein mutation in conradi-hünermann-happle syndrome representing plaque-type psoriasis.

Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata which primarily affects the skin, bones, and eyes. CDPX2 patients display skin defects, including ichthyotic lesions, follicular atrophoderma, cicatricial alopecia, and less frequently ichthyosiform erythroderma, cataracts, and skeletal abnormalities consisting of short stature, asymmetric shortening of the limbs, epiphyseal stippling, and craniofacial defects. CDPX2 results from mutations in emopamil binding protein (EBP) gene. The aim of our study is to identify EBP mutation in a unique case of Conradi-Hünermann-Happle syndrome with rare psoriasiform lesions.

Genetic background of supernumerary teeth.

Supernumerary teeth (ST) are odontostomatologic anomaly characterized by as the existence excessive number of teeth in relation to the normal dental formula. This condition is commonly seen with several congenital genetic disorders such as Gardner's syndrome, cleidocranial dysostosis and cleft lip and palate. Less common syndromes that are associated with ST are; Fabry Disease, Ellis-van Creveld syndrome, Nance-Horan syndrome, Rubinstein-Taybi Syndrome and Trico-Rhino-Phalangeal syndrome. ST can be an important component of a distinctive disorder and an important clue for early diagnosis. Certainly early detecting the abnormalities gives us to make correct management of the patient and also it is important for making well-informed decisions about long-term medical care and treatment. In this review, the genetic syndromes that are related with ST were discussed.